On Behalf of the SGI-110 Investigative Team

Transcription

1 First clinical results of a randomized phase 2 study of SGI-110, a novel subcutaneous hypomethylating agent, in 102 patients with Intermediate or High Risk MDS or CMML n Behalf of the SGI-110 Investigative Team Guillermo Garcia Manero 1, Ellen Ritchie 2, Katherine Walsh 3,Michael Savona 4, Patricia Kropf 5, Casey Connell 6, Raoul Tibes 7, Naval Daver 1, Elias Jabbour 1, Scott Lunin 8, Todd Rosenblat 9, Karen Yee 10, Wendy Stock 11, Elizabeth Griffiths 12, Joseph Mace 13, Nikola Podoltsev 14, Jesus Berdeja 4, Jean-Pierre Issa 15, Woonbok Chung 15, Sue Naim 16, Pietro Taverna 16, Yong Hao 16, Mohammad Azab 16,Hagop Kantarjian 1, Gail Roboz 2 1 MD Anderson Cancer Center, Houston, TX, 2 Weill Cornell Medical College, New York, NY, 3 The hio State University, Columbus, H, 4 Sarah Cannon Research Institute/Tennessee ncology, Nashville, TN, 5 Fox Chase Cancer Center, Philadelphia, PA, 6 USC Keck School of Medicine, University of Southern California, Los Angeles, CA, 7 Mayo Clinic Arizona, Scottsdale, AZ, 8 Florida Cancer Specialist, Englewood, FL, 9 New York Presbyterian/Columbia University Medical Center, New York, NY, 10 Princess Margaret Cancer Center, Toronto, Canada, 11 University of Chicago Medical Center, Chicago, IL, 12 Roswell Park Cancer Institute, Buffalo, NY, 13 Florida Cancer Specialists, St Petersburg, FL, 14 Yale University School of Medicine, New Haven, CT, 15 Fels Institute, Temple University, Philadelphia, PA, 16 Astex Pharmaceuticals Inc., Dublin, CA.

2 Background: DNA Methylation in MDS/AML DNA methylation is an epigenetic process tightly linked to gene expression MDS and AML are characterized by frequent DNA methylation changes and mutations in epigenetic genes (e.g. TET2, DNMT3a, EZH2) First generation hypomethylating agents (azacitidine, decitabine) have demonstrated clinical activity in MDS and AML 2

3 SGI-110 Background A Second Generation Hypomethylating Agent Decitabine is rapidly eliminated by Cytidine Deaminase, limiting drug exposure time to cancer cells in vivo SGI-110 is a Dinucleotide of Decitabine and Deoxyguanosine that prolongs the in vivo exposure of decitabine by protecting it from deamination Prolonged decitabine in vivo exposure may translate to better efficacy NH 2 H NH 2 N N N H Decitabine + N NH H N H N NH 2 Deoxyguanosine Guanosine H + N a - N P N N N N SGI-110 NH N NH 2 H SGI

4 SGI-110 Phase 1 PK Prolonged Exposure time and t ½ of decitabine compared to decitabine IV 150 SGI-110 Dose (mg/m 2 ) Decitabine, ng/ml IV decitabine, 20 mg/m^2, simulated Time, hr 6 8 Decitabine exposure window after SC SGI-110 is more than double (8hr+) compared to decitabine 20 mg/m 2 1-hr IV infusion (3-4h, simulated) Prolonged decitabine t 1/2 (up to 2 hr vs hr for decitabine IV) due to protracted release from SGI-110 Lower decitabine Cmax compared to decitabine IV 4

5 SGI-110 Phase 1 PD Potent dose-dependent LINE1 DNA Demethylation 5.00 Daily x LINE1 demethylation (%) Day 3 mg/m2 3mg/m(n=4) 2 (n=4) 9 mg/m2 9mg/m(n=4) 2 (n=4) 18 mg/m2 18mg/m(n=3) 2 (n=3) 36 mg/m2 36mg/m(n=5) 2 (n=5) 60 mg/m2 60mg/m(n=5) 2 (n=5) 90 mg/m2 90mg/m 2 (n=4) mg/m mg/m2 (n= 2 (n=10) LINE-1 demethylation increased with dose up to 60 mg/m 2 Dailyx5 Maximum demethylation achieved at 60 mg/m 2 Dailyx5 (BED) MTD in MDS patients reached at 90 mg/m 2 Dailyx5 5

6 Randomized Phase 2 Study of SGI-110 in MDS/CMML 1 Major Eligibility Previously Treated MDS/CMML or Treatment Naïve MDS/CMML IPSS Int-1,2 and HR ECG PS 0-2 Adequate hepato-renal function R A N D M I Z A T I N Biologically Effective Dose 60 mg/m 2 daily x 5 Highest Well Tolerated Dose 90 mg/m 2 daily x 5 IWG 2006 MDS Response Criteria Treatment continued until unacceptable toxicity, disease progression Primary Endpoint: verall Response Rate (CR, PR, mcr, HI) Secondary Endpoints: Transfusion independence, LINE-1 demethylation, time to AML, overall survival 1 Data presented with data cutoff end of July

7 SGI-110: Patients Characteristics By Dose Patient Characteristics 60 mg/m 2 (n=53) 90 mg/m 2 (n=49) Median Age, (range) 71.7 (18-86) 72.5 (52-89) Gender, M n (%) 37 (70) 30 (61) ECG PS %: 0/1/2 23/62/15 24/63/12 Disease Category (IPSS) n (%) Int-1 Int-2 High Risk CMML 16 (30) 7 (13) 15 (28) 15 (28) 11 (22) 11 (22) 18 (37) 7 (14) Median BM Blast % (range) 4 (0-18) 8 (0-19) Median Neutrophils (10 9 /L) Median Platelets (10 9 /L) Median Hb (g/dl) Prior decitabine or azacitidine n(%) 25 (47) 27 (55) Disease Status (n) Previously Treated MDS Tx naïve MDS

8 SGI-110: Patients Characteristics By MDS Status Patient Characteristics Prev. Treated (n=53) Tx Naïve (n=49) Median Age, (range) 72.5 (52-89) 71.7 (18-85) Gender, M n (%) 32 (60) 35 (71) ECG PS %: 0/1/2 21/58/21 27/67/6 Disease Category (IPSS) n (%) Int-1 Int-2 High Risk CMML 4 (8) 13(25) 24 (45) 10 (19) 23 (47) 5 (10) 9 (18) 12 (24) Median BM Blast % (range) 8 (0-19) 3 (0-14) Median Neutrophils (10 9 /L) Median Platelets (10 9 /L) Median Hb (g/dl) Prior decitabine or azacitidine n(%) 51 (96) 1 (2) 1 Randomized Dose (n) 60 mg/m2 90 mg/m Patient received only 1 prior cycle of HMA 8

9 SGI-110: Treatment Intensity and Number of Cycles 1 By Dose Median # (range) % Cycles Dose Delayed % of Cycles Dose Reduced 60 mg/m2 4 (1-22) 33% 19% 90 mg/m2 4 (1-15) 36% 22% By MDS Status Median # (range) % Cycles Dose Delayed % of Cycles Dose Reduced Prev Treated 4 (1-11) 37% 23% Tx naive 5 (1-22) 36% 21% 38 of 102 patients are still ongoing treatment (37%) 1 Majority of Cycles completed on time and with intended dose 9 1 At time of data cutoff

10 SGI-110: Best Response 1 By Dose Response 60 mg/m 2 Category 1 (n=53) 90 mg/m 2 (n=49) Response rate n (%) Response rate n (%) CR 4 (7.5) 5 (10.2) mcr 6 (11.3) 6 (12.2) HI 4 (7.5) 6 (12.2) CR+mCR 10 (18.8) 11 (22.4) verall Response Rate 14 (26.4) 17 (34.7) 1 International Working Group 2006 MDS Response Criteria 10

11 SGI-110: Best Response 1 By MDS Status Response Category 1 Prev Treated (n=53) Tx Naïve (n=49) Response rate n (%) Response rate n (%) CR 2 (3.8) 7 (14.3) mcr 9 (17.0) 3 (6.1) HI 1 (1.9) 9 (18.4) CR+mCR 11 (20.8) 10 (20.4) verall Response Rate 12 (22.7) 19 (38.8) 1 International Working Group 2006 MDS Response Criteria 11

12 SGI-110: LINE-1 Demethylation in Cycle % Demethylation mg/m² n= mg/m² n=48 Max Demethylation -25% -29% Days 13

13 SGI-110: Transfusion Independence 60 mg/m2 (n=53) 90 mg/m2 (n=49) Baseline RBCs Transfusion dependent 8-week RBCs Transfusion Independent n (%) Baseline Platelets Transfusion dependent 8-week Platelets Transfusion Independent n (%) 27/53 (51%) 24/49 (49%) 7/27 (26%) 5/24 (21%) 13/53 (25%) 15/49 (31%) 4/13 (31%) 5/15 (33%) 14

14 SGI-110: Adverse Events Grade 3 in 10% of Patients 1 Adverse Event 60 mg/m2 (n=53) Grade 3 AEs % 90 mg/m2 (n=49) Grade 3 AEs % Anemia 38% 37% Febrile Neutropenia 32% 33% Neutropenia 42% 49% Thrombocytopenia 38% 51% Pneumonia 13% 20% Leukopenia 11% 12% 60 mg/m2 (n=53) 90 mg/m2 (n=49) 8-week all-cause mortality n (%) 2 (3.8%) 1 (2.0%) 1 Regardless of relationship to SGI

15 Conclusions SGI-110 is a new HMA with clinical activity in MDS/CMML 14% CR and 39% verall response rate in Treatment Naïve MDS/CMML 21% CR+mCR and in Previously Treated MDS/CMML No significant difference between 60 and 90 mg/m2 Dailyx5 doses Potent demethylation and Transfusion independence with both doses Both doses well tolerated: slightly higher Grade 3 Pneumonia and Thrombocytopenia with 90 mg/m2 compared to 60 mg/m2 Follow up for Survival is ongoing Future Development in MDS and AML: MDS: Data warrant further Phase 3 development particularly in Previously Treated MDS AML: Phase 3 in Treatment Naïve AML not candidate for intensive chemotherapy is being initiated 15

16 Acknowledgements Hagop Kantarjian, MD Guillermo Garcia-Manero, MD Farhad Ravandi, MD Elias Jabbour, MD Naval Daver, MD Jean Pierre Issa, MD Patricia Kropf, MD Woonbok Chung, PhD Todd Rosenblatt, MD Joseph Jurcic, MD, PhD Azra Raza, MD Michael Savona, MD Jesus Berdeja, MD Raoul Tibes, MD, PhD Ruben Mesa, MD Gail Roboz, MD Eric Feldman, MD Ellen Ritchie, MD Steve Baylin, MD Peter Jones, PhD Jean Pierre Issa, MD Nikolai Podoltsev, MD, PhD Katherine Walsh, MD William Blum, MD Wendy Stock, MD Richard Larson, MD Elizabeth Griffiths, MD SGI-110 American Society of Hematology 2013 Karen Yee, MD Aaron Schimmer, MD Casey Connell, MD Scott Lunin, MD Joseph Mace, MD Mohammad Azab, MD Yong Hao, PhD Xiang Yao Su Sue Naim Pietro Taverna, PhD 16